Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genetic architecture of gene regulation in Indonesian populations identifies QTLs associated with global and local ancestries.

ABSTRACT: Lack of diversity in human genomics limits our understanding of the genetic underpinnings of complex traits, hinders precision medicine, and contributes to health disparities. To map genetic effects on gene regulation in the underrepresented Indonesian population, we have integrated genotype, gene expression, and CpG methylation data from 115 participants across three island populations that capture the major sources of genomic diversity in the region. In a comparison with European datasets, we identify eQTLs shared between Indonesia and Europe as well as population-specific eQTLs that exhibit differences in allele frequencies and/or overall expression levels between populations. By combining local ancestry and archaic introgression inference with eQTLs and methylQTLs, we identify regulatory loci driven by modern Papuan ancestry as well as introgressed Denisovan and Neanderthal variation. GWAS colocalization connects QTLs detected here to hematological traits, and further comparison with European datasets reflects the poor overall transferability of GWAS statistics across diverse populations. Our findings illustrate how population-specific genetic architecture, local ancestry, and archaic introgression drive variation in gene regulation across genetically distinct and in admixed populations and highlight the need for performing association studies on non-European populations.

SUBMITTER: Natri HM

PROVIDER: S-EPMC8764200 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Chromatin activity identifies differential gene regulation across human ancestries.

Project description:BackgroundCurrent evidence suggests that cis-regulatory elements controlling gene expression may be the predominant target of natural selection in humans and other species. Detecting selection acting on these elements is critical to understanding evolution but remains challenging because we do not know which mutations will affect gene regulation.ResultsTo address this, we devise an approach to search for lineage-specific selection on three critical steps in transcriptional regulation: chromatin activity, transcription factor binding, and chromosomal looping. Applying this approach to lymphoblastoid cells from 831 individuals of either European or African descent, we find strong signals of differential chromatin activity linked to gene expression differences between ancestries in numerous contexts, but no evidence of functional differences in chromosomal looping. Moreover, we show that enhancers rather than promoters display the strongest signs of selection associated with sites of differential transcription factor binding.ConclusionsOverall, our study indicates that some cis-regulatory adaptation may be more easily detected at the level of chromatin than DNA sequence. This work provides a vast resource of genomic interaction data from diverse human populations and establishes a novel selection test that will benefit future study of regulatory evolution in humans and other species.

| S-EPMC10789071 | biostudies-literature

Genetic regulation of fetal hemoglobin across global populations.

Project description:Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.

| S-EPMC10055601 | biostudies-literature

On Using Local Ancestry to Characterize the Genetic Architecture of Human Traits: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations.

Project description:Understanding the nature of the genetic regulation of gene expression promises to advance our understanding of the genetic basis of disease. However, the methodological impact of the use of local ancestry on high-dimensional omics analyses, including, most prominently, expression quantitative trait loci (eQTL) mapping and trait heritability estimation, in admixed populations remains critically underexplored. Here, we develop a statistical framework that characterizes the relationships among the determinants of the genetic architecture of an important class of molecular traits. We provide a computationally efficient approach to local ancestry analysis in eQTL mapping while increasing control of type I and type II error over traditional approaches. Applying our method to National Institute of General Medical Sciences (NIGMS) and Genotype-Tissue Expression (GTEx) datasets, we show that the use of local ancestry can improve eQTL mapping in admixed and multiethnic populations, respectively. We estimate the trait variance explained by ancestry by using local admixture relatedness between individuals. By using simulations of diverse genetic architectures and degrees of confounding, we show improved accuracy in estimating heritability when accounting for local ancestry similarity. Furthermore, we characterize the sparse versus polygenic components of gene expression in admixed individuals. Our study has important methodological implications for genetic analysis of omics traits across a range of genomic contexts, from a single variant to a prioritized region to the entire genome. Our findings highlight the importance of using local ancestry to better characterize the heritability of complex traits and to more accurately map genetic associations.

| S-EPMC6562007 | biostudies-literature

Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries.

Project description:Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.

| S-EPMC10290755 | biostudies-literature

The Genetic Architecture of Emerging Fungicide Resistance in Populations of a Global Wheat Pathogen.

Project description:Containing fungal diseases often depends on the application of fungicidal compounds. Fungicides can rapidly lose effectiveness due to the rise of resistant individuals in populations. However, the lack of knowledge about resistance mutations beyond known target genes challenges investigations into pathways to resistance. We used whole-genome sequencing data and association mapping to reveal the multilocus genetic architecture of fungicide resistance in a global panel of 159 isolates of Parastagonospora nodorum, an important fungal pathogen of wheat. We found significant differences in azole resistance among global field populations. The populations evolved distinctive combinations of resistance alleles which can interact when co-occurring in the same genetic background. We identified 34 significantly associated single nucleotide polymorphisms located in close proximity to genes associated with fungicide resistance in other fungi, including a major facilitator superfamily transporter. Using fungal colony growth rates and melanin production at different temperatures as fitness proxies, we found no evidence that resistance was constrained by genetic trade-offs. Our study demonstrates how genome-wide association studies of a global collection of pathogen strains can recapitulate the emergence of fungicide resistance. The distinct complement of resistance mutations found among populations illustrates how the evolutionary trajectory of fungicide adaptation can be complex and challenging to predict.

| S-EPMC7846115 | biostudies-literature

Properties of global- and local-ancestry adjustments in genetic association tests in admixed populations.

Project description:Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry-adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global-ancestry adjustment should be used for screening, but local-ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.

| S-EPMC5811405 | biostudies-literature

Local and global ancestry inference and applications to genetic association analysis for admixed populations.

Project description:Genetic association studies in recently admixed populations offer exciting opportunities to identify novel variants underlying phenotypic diversity. At the same time, genetic heterogeneity resulting from population admixture has to be accounted for to ensure validity of association tests. The whole-genome sequence data and the genome-wide single-nucleotide polymorphism chip data for Mexican American individuals provided by Genetic Analysis Workshop 18 (GAW18) presents a unique opportunity to evaluate and compare methods for the statistical analysis of admixed genetic data. We summarize here the five contributions from the GAW18 working group on admixture mapping and adjusting for admixture. Although group members considered a variety of research topics, the general theme was inference and consideration of ancestry admixture in genetic analyses. The topics considered can be grouped into three categories: (1) global and local ancestry inference and estimation, (2) association and admixture mapping, and (3) genotype imputation in admixed samples. We describe the approaches that were used and the most relevant findings from each contribution. We also provide insight into the strengths and limitations of the state-of-the-art methods considered for genetic analyses in admixed populations.

| S-EPMC4339867 | biostudies-literature

Genetic Analysis of Local Pig Populations in Ghana

Project description:The Ashanti Dwarf Pig (ADP) of Ghana is an endangered pig breed with hardy and disease resistant traits. Characterisation of animal genetic resources provides relevant data for their conservation and sustainable use for food security and economic development. We investigated the origin and phylogenetic status of the local ADP of Ghana and their crosses with modern commercial breeds based on mtDNA, MC1R and Y-chromosome sequence polymorphisms, and genome-wide SNP genotyping. The study involved 164 local pigs sampled from the three agro-ecological zones of Ghana. Analyses of the mitochondrial D-loop region and Y-chromosome sequences revealed that the ADP of Ghana has both European and Asian genetic signatures. The ADP also displays considerable variation in the MC1R gene. Black coat colour is the most predominant within the breed, with the dominant black alleles of both Asian and European origin contributing to the majority of alleles in the pool. European alleles for spotting are present at a low frequency in the sample set, and may account for the occurrence of spotted piglets in some APD litters. Other colour variants may be due to epistatic interactions with additional coat colour loci, or mutations. The wide variations in coat colour patterns suggest that morphology alone cannot be used to adequately characterise Ghanaian local pigs. PCA analysis of SNP genotyping data revealed a strong location effect on clustering of local Ghanaian pigs. Based on this work, we recommend that further studies be carried out on more local pigs to find out the effect of admixture on important adaptive and economic traits of the ADP and other local Sus breeds in Africa to help develop a sustainable conservation programmes to prevent the decline of this genetic resource.

2017-03-08 | GSE84604 | GEO

A genome-wide association and prediction study in grapevine deciphers the genetic architecture of multiple traits and identifies genes under many new QTLs.

Project description:To cope with the challenges facing agriculture, speeding-up breeding programs is a worthy endeavor, especially for perennial species such as grapevine, but requires understanding the genetic architecture of target traits. To go beyond the mapping of quantitative trait loci in bi-parental crosses, we exploited a diversity panel of 279 Vitis vinifera L. cultivars planted in 5 blocks in the vineyard. This panel was phenotyped over several years for 127 traits including yield components, organic acids, aroma precursors, polyphenols, and a water stress indicator. The panel was genotyped for 63k single nucleotide polymorphisms by combining an 18K microarray and genotyping-by-sequencing. The experimental design allowed to reliably assess the genotypic values for most traits. Marker densification via genotyping-by-sequencing markedly increased the proportion of genetic variance explained by single nucleotide polymorphisms, and 2 multi-single nucleotide polymorphism models identified quantitative trait loci not found by a single nucleotide polymorphism-by-single nucleotide polymorphism model. Overall, 489 reliable quantitative trait loci were detected for 41% more response variables than by a single nucleotide polymorphism-by-single nucleotide polymorphism model with microarray-only single nucleotide polymorphisms, many new ones compared with the results from bi-parental crosses. A prediction accuracy higher than 0.42 was obtained for 50% of the response variables. Our overall approach as well as quantitative trait locus and prediction results provide insights into the genetic architecture of target traits. New candidate genes and the application into breeding are discussed.

| S-EPMC9258538 | biostudies-literature

Local Order within Global Disorder: Synaptic Architecture of Visual Space.

Project description:Substantial evidence at the subcellular level indicates that the spatial arrangement of synaptic inputs onto dendrites could play a significant role in cortical computations, but how synapses of functionally defined cortical networks are arranged within the dendrites of individual neurons remains unclear. Here we assessed one-dimensional spatial receptive fields of individual dendritic spines within individual layer 2/3 neuron dendrites. Spatial receptive field properties of dendritic spines were strikingly diverse, with no evidence of large-scale topographic organization. At a fine scale, organization was evident: neighboring spines separated by less than 10 ?m shared similar spatial receptive field properties and exhibited a distance-dependent correlation in sensory-driven and spontaneous activity patterns. Fine-scale dendritic organization was supported by the fact that functional groups of spines defined by dimensionality reduction of receptive field properties exhibited non-random dendritic clustering. Our results demonstrate that functional synaptic clustering is a robust feature existing at a local spatial scale. VIDEO ABSTRACT.

| S-EPMC5868972 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data